This invention concerns biologically active 8-aza-13-thiaprostanoids.
There are many references in the literature to prostanoids, a term which is generic to natural and synthetic prostaglandins and prostaglandin-like compounds. It is well known in connection with these prostanoids that even slight differences in chemical structures or stereochemical configurations will have profound effects on biological activity.
Prostanoids have a five-membered ring bearing relatively lengthy substituents on adjacent ring atoms. In most of the known prostanoids, the rings are carbocyclic; in a few of these compounds one of the side chains bears a sulfur atom in the C.sub.13 position. Representative of the prostanoids that contain a carbocyclic ring and a sulfur atom in a side chain are those described in the following publications.
U.S. Pat. No. 4,209,639 discloses prostaglandins having the formula: ##STR3## wherein Y is a divalent radical selected from the group consisting of ##STR4## R.sub.2 is selected from the group consisting of H, OH, and lower alkanoyloxy; R.sub.1 is hydrogen or an alkyl of 1 to 12 carbons; R.sub.3 is hydrogen, an alkyl of 4 to 7 carbons or a phenoxymethyl group in which the phenyl ring is optionally substituted; X is a divalent radical comprising carbon, hydrogen, and OH; and Z is a divalent radical selected from a number of substituent groups, none of which contains nitrogen.
U.S. Pat. No. 4,309,441 discloses prostaglandins having the formula: ##STR5## wherein A is --CO-- or --CHOH--; B is --CH.sub.2 CH.sub.2 -- or --CH.dbd.CH--; Q is 1,4-phenylene or 1,4-naphthylene; R.sup.1 is H or OH; R.sup.2 is H or CH.sub.3 ; R.sup.3 is alkyl with 1 to 8 carbon atoms or alkyl with 1 to 8 carbon atoms substituted by (a) phenyl, (b) phenyl substituted by at least one of CH.sub.3, F, Cl, Br, OH, OCH.sub.3 or CF.sub.3, (c) phenoxy or (d) phenoxy substituted by at least one of CH.sub.3, F, Cl, Br, OH, OCH.sub.3 or CF.sub.3 ; and R.sup.4 is NH.sub.2, CH.sub.3, phenyl, p-acetylaminophenyl, p-benzoylaminophenyl or pentylamino. These prostaglandins contain no aza nitrogen.
Novak et al., in Tetrahedron, Vol. 38, No. 1, pages 153 to 159 (1982) also disclose prostaglandins that contain no nitrogen: ##STR6## wherein X and Y are CH.sub.2 --CH.sub.2 or ##STR7## and R and R' are H or CH.sub.3.
Two recent publications that discuss the phenomenon of cytoprotection by prostaglandins are Robert et al., Gastroent., 77, 433 to 443 (1979) and Robert, Scand. J. Gastroent., 16, Suppl. 67, 223 to 227 (1981). These publications describe several of the uses including antiulcer use, to which the compounds of this invention may be put. In this regard, see especially pages 442 to 443, and 226 to 227, respectively.
The prostanoids now described differ from those disclosed in these publications primarily in that they combine the following structural features (designated by conventional prostanoid numbering): a single nitrogen atom at position 8 in a heterocyclic five-membered ring and a carbonyl group in the five-membered ring at position 9 (making them lactams).
Other representative heterocycle-based prostanoids that do not, however, contain sulfur are the aza- and diaza-prostanoids disclosed in U.S. Pat. No. 3,873,566 (Scribner), U.S. Pat. No. 3,975,399 (DeFranco and Scribner), U.S. Pat. No. 4,003,911 and U.S. Pat. No. 4,032,533 (Scribner), U.S. Pat. No. 4,113,873 (Himizu), U.S. Pat. No. 4,177,346 (Nelson), U.S. Pat. No. 4,211,876 (Scribner), and Belgium Pat. No. 854,268 (Hoechst).